This invention relates to a series of C-6-substituted pyrido[1,2-a]benzimidazole derivatives and to pharmaceutical compositions containing them. The compounds are ligands for the BZD site on GABA-A receptors and are thus useful for the treatment of disorders of the central nervous system.
The gamma-aminobutyric acid-A (GABA-A receptor) is the most abundant inhibitory receptor in the brain of mammals. It is comprised of a heteropolymeric structure that forms a chloride ion channel, and bears multiple recognition sites for the binding of modulatory molecules. The binding of GABA to its specific recognition site on the GABA-A receptor opens the ion channel and allows chloride ions to flow into the nerve cell. This action hyperpolarizes the cell membrane of that neuron and thereby makes the cell less reactive to excitatory stimuli. The chloride ion current may also be regulated by various drugs that serve as positive or negative modulators of the GABA-A receptor (Smith and Olsen, Trends Pharm. Sci., 1995, 16, 162; Stephenson, Biochem. J., 1995, 310, 1). The so-called benzodiazepine (BZD) receptor is a site for such allosteric modulators on the GABA-A receptor. This site mediates two opposing effects, one that amplifies the action of GABA (xe2x80x9cpositivexe2x80x9d efficacy) and the other that reduces the action of GABA (xe2x80x9cnegativexe2x80x9d efficacy). Agents facilitating GABA-receptor/chloride ion-channel functions via the BZD site are referred to as agonists, while agents reducing such function are referred to as inverse agonists. Antagonists at this site block the effects of agonists or inverse agonists by competitively inhibiting their binding. It is thus possible to have a series of compounds in which members equally bind to the BZD site but have equal and opposite regulatory effects on the GABA-A receptor/chloride ion channel. Also, within the series a continuum of activity is possible (Takada, S. et al. J. Med. Chem. 1988, 31, 1738). Thus, BZD receptor ligands can induce a wide spectrum of pharmacological effects ranging from muscle relaxant, hypnotic, sedative, anxiolytic, and anticonvulsant activities, produced by full or partial agonists (xe2x80x9cpositivexe2x80x9d), to the proconvulsant, anti-inebriant, and anxiogenic activities, produced by inverse agonists (xe2x80x9cnegativexe2x80x9d). (A further understanding of this area can be gleaned from: Mohler, H. Arzneim.-Forsch./Drug Res. 1992, 42 (2a), 211; Haefely, W. et al., Advances in Drug Research, Academic Press, vol. 14, 985, pp. 165-322; Skolnick, P. et al. GABA and Benzodiazepine Receptors, Squires, R., Ed., 1987, pp. 99-102 and references cited therein.)
The benzodiazepines are a class of compounds which bind to the BZD receptor with high affinity. Most of the drugs in use are agonist-type ligands for the receptor. Such compounds are generally useful for their anticonvulsant, anxiolytic, sedative, and muscle relaxant effects. Antagonists of the BZD binding site are thus useful for the treatment of benzodiazepine drug overdose and inverse agonists are useful in managing alcoholism.
The present invention is concerned with novel compositions of matter and their use. Compounds having some structural similarity to those of the present invention are described in Rida, S. M. et al. J. Het Chem. 1988. 25, 1087; Soliman, F. S. G. et al. Arch. Pharm. 1984, 317, 951; Volovenko, Y. M. et al. U.S.S.R. Patent SU 1027166 (Chem Abs. 99(25) 212524t; Ohta, S. et al. Heterocycles 1991, 32, 1923; Ohta, S. et al. Chem. Pharm. Bull. 1991, 39, 2787. In addition, related compounds are disclosed in U.S. Pat Nos. 5,817,668, 5,817,668, 5,639,760, 5,521,200 and 5,922,731. The novel compounds differ from the prior art compounds in that they contain a ring substituent in the 6-position of the A ring.
The present invention is directed to compounds of the following formula: 
wherein R1, R2, R3, X and n are as defined hereinafter. The compounds of Formula 1 are useful in treating central nervous system disorders. The compounds are ligands for the BZD binding site on GABA-A receptors and are thus useful as muscle relaxants, hypnotics/sedatives including sleep-aids, anxiolytics, antidepressants, anticonvulsants/antiepileptics, anti-inebriants, and antidotes for drug overdose.
The present invention also comprises pharmaceutical compositions containing one or more of the compounds of formula 1 as the active ingredient and methods for the treatment of disorders to the central nervous system including convulsions such as epileptic seizures, anxiety, depression, muscular spasms, sleep disorders, attention deficit hyperactivity disorder (ADHD) and benzodiazepine overdoses.
More particularly, the present invention is directed to compounds of the general formula: 
wherein:
R1 is independently selected from the group consisting of hydrogen; C1-8alkyl (including C1-8 straight chain alkyl and C3-8 branched chain alkyl); halogen; perfluoroC14alkyl; hydroxy; C1-4alkoxy; amino; di(C1-4alkyl)amino; aminoC1-4alkylamino; nitro; C1-4alkoxycarbonyl; and C1-4alkylthio; There may be up to three independent R1 substituents on the ring (n=1-3); R1 is preferably hydrogen, C1-8alkyl, halogen or C1-4alkoxy;
R2 is selected from the group consisting of hydrogen; C1-6 alkyl (including C1-6 straight chain alkyl and C3-6 branched chain alkyl); aralkyl; heteroaryl(C14)alkyl; (R4)2N(CH2)p wherein R4 is the same or different and is independently selected from H, C1-4alkyl, aralkyl, aryl or substituted aryl wherein the substituents are independently selected from C1-4alkyl, C1-4alkoxy, nitro, amino or halo, and p is 1-5; or R4 together with the nitrogen to which they are attached may form a heterocyclic group selected from piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrazolyl, triazolyl, indolyl, indolinyl, imidazolyl, benzimidazolyl, pyrrolyl or indazolyl, preferably morpholinyl, piperidinyl or pyrrolidinyl; R5O(CH2)p wherein R5 is selected from C1-4alkyl, aralkyl, aryl or substituted aryl wherein the substituents are independently selected from C1-4alkyl, C1-4alkoxy, nitro, amino or halo and p is 1-5; and R5S(CH2)p; wherein R5 and p are as defined above; R2 is preferably H or C1-6alkyl;
R3 is independently selected from the group consisting of aryl; substituted aryl, wherein the substituents are selected from C1-8alkyl, halo, perfluoroC1-4alkyl, hydroxy, C1-4alkoxy, amino, di(C1-4alkyl)amino, C1-4alkoxycarbonyl, aminoC2-6alkoxy, C1-8alkylaminoC2-6alkoxy, di(C1-8alkyl)aminoC2-6alkoxy, or C1-4alkylthio; a heteroaryl group selected from pyridyl; thiazolyl; thiophenyl; furyl; indolyl; imidazolyl; benzothiophenyl; pyridazinyl; pyrimidinyl; indolyl; indolinyl; quinolinyl; indazolyl; benzofuryl; triazinyl; pyrazinyl; isoquinolinyl; isoxazolyl; thiadiazolyl; benzothiazolyl; triazolyl; or benzotriazolyl; a substituted heteroaryl group wherein the substituent is selected from oxo, halo, perfluoroC1-4alkyl, nitro, amino, C1-4alkylthio, C1-4alkoxy, C1-4alkylamino, di(C1-4)alkylamino, carboxy or C1-4alkoxycarbonyl; and cycloalkyl having 3-8 carbon atoms; R3 is preferably aryl, haloaryl, C1-4alkoxyaryl or heteroaryl;
X is a heterocyclic or carbocyclic ring selected from the group consisting of piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperazinyl, imidazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxazolinyl, triazolyl, tetrazolyl, oxadiazolyl, dioxaazaspirodecanyl, thiadiazolyl, purinyl, benzimidazolyl, benzothiophenyl, benzothiazolyl, indolyl; cyclo(C3-8)alkyl; phenyl; and naphthyl; a substituted heterocyclic, carbocyclic, or aryl ring wherein the substituents are independently selected from C1-8alkyl (including C1-8 straight chain alkyl and C3-8 branched chain alkyl), halogen, perfluoroC1-4alkyl, hydroxy, amino, nitro, oxo, C1-4alkoxy, C1-4alkylamino, di(C1-4alkyl)amino, C1-4alkoxycarbonyl, C1-4alkoxyC1-4alkylcarbonyl, aryl, substituted aryl wherein the substituents are independently selected from C1-4alkyl, C1-4alkoxy, nitro, amino, or halo; heteroaryl and C1-4alkylthio; preferably, X is a heterocyclic ring;
and pharmaceutically acceptable salts thereof.
As used herein unless otherwise noted the terms xe2x80x9calkylxe2x80x9d and xe2x80x9calkoxyxe2x80x9d whether used alone or as part of a substituent group, include straight and branched chains having 1-8 carbon atoms. For example, alkyl radicals include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, 2-methyl-3-butyl, 1-methylbutyl, 2-methylbutyl, neopentyl, hexyl, 1-methylpentyl, 3-methylpentyl. Alkoxy radicals are oxygen ethers formed from the previously described straight or branched chain alkyl groups. The term xe2x80x9carylxe2x80x9d is intended to include phenyl and naphthyl. The term xe2x80x9chaloxe2x80x9d, unless otherwise indicated, includes bromo, chloro, fluoro and iodo. The term xe2x80x9ccycloalkylxe2x80x9d is intended to include cycloalkyl groups having 3-8 carbon atoms. The term xe2x80x9caralkylxe2x80x9d is intended to include an aryl group attached to a C1-8alkyl group, preferably a C1-4alkyl group (e.g., benzyl, phenylethyl).
The term xe2x80x9cheteroarylxe2x80x9d is intended to include an aromatic ring containing at least one heteroatom selected from sulfur, oxygen or nitrogen, optionally containing one to three additional heteroatoms independently selected from sulfur, oxygen ot nitrogen, such as, but not limited to, pyridyl, thiazolyl, thiophenyl, furyl, indolyl, imidazolyl, benzothiophenyl, pyridazinyl, pyrimidinyl, indolinyl, quinolinyl, indazolyl, benzofuryl, isoquinolinyl, triazinyl, pyrazinyl, isoxazolyl, thiadiazolyl, benzothiazolyl, triazolyl, benzotriazolyl, oxazolyl, and the like.
The term xe2x80x9cheterocyclic ringxe2x80x9d is intended to include a saturated, partially unsaturated, partially aromatic or aromatic ring structure containing at least one heteroatom selected from sulfur, oxygen or nitrogen, optionally containing one to three additional heteroatoms independently selected from sulfur, oxygen or nitrogen, such as, but not limited to piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, pyrazolyl, triazolyl, indolyl, benzimidazolyl, pyrrolyl, indazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, isothiazolyl, oxazolyl, dioxaazaspirodecanyl, thiadiazolyl, purinyl, benzimidazolyl, benzothiphenyl, benzothiazolyl, indolyl, and the like. The term xe2x80x9ccarbocyclic ringxe2x80x9d is intended to include saturated, partially unsaturated, partially aromatic or aromatic ring structure such as, but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, naphthyl, and the like.
When a particular group (e.g., aryl, heteroaryl) is substituted, that group may have one or more substituents (preferably, one to five, more preferably, one to three, most preferably, one or two substituents) independently selected from the listed substituents. With reference to substituents, the term xe2x80x9cindependentlyxe2x80x9d means that when more than one of such substituent is possible, such substituents may be the same or different from each other.
As used herein, the abbreviation xe2x80x9cPhxe2x80x9d shall mean phenyl, xe2x80x9cMexe2x80x9d shall mean methyl, xe2x80x9cEtxe2x80x9d shall mean ethyl, xe2x80x9cMeOHxe2x80x9d shall mean methanol, xe2x80x9cEtOHxe2x80x9d shall mean ethanol and xe2x80x9cEtOAcxe2x80x9d shall mean ethyl acetate.
Those compounds of the present invention which contain a basic moiety can be converted to the corresponding acid addition salts by techniques known to those skilled in the art. Suitable acids which can be employed for this purpose include hydrochloric, hydrobromic, hydriodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, cinnamic, mandelic, methanesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic, 2-phenoxybenzoic, 2-acetoxybenzoic, or saccharin, and the like. In general, the acid addition salts can be prepared by reacting the free base of compounds of formula 1 with the acid and isolating the salt.
Where the compounds according to this invention have at least one chiral center, they may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention.
The compounds of Formula 1 are prepared as outlined in the following 
More specifically, an appropriately substituted benzoic acid (24) was treated with sodium azide, or under other suitable conditions known to promote a Curtius type rearrangement, to form a substituted nitro aniline (25). Treatment of the nitro aniline (25) with an appropriate nucleophile such as, for example, piperidine, imidazole, thiazole or morpholine, gives the chlorine displaced nitroaniline product (26 in the case of piperidine). The reaction is generally carried out at elevated temperatures (100-125xc2x0 C.). Alternatively, carbon-carbon bond formation can be achieved by suitable protection of the aniline nitrogen of 25 followed by organometallic coupling reactions, e.g. organocopper coupling to incorporate phenyl substitution and Grignard reagent formation followed by condensation with ketones, elimination, and reduction for saturated carbocyclics. In the case of piperidine substitution, nitroaniline 26 is reacted with acrylonitrile in a suitable solvent such as dioxane, tetrahydrofuran or chloroform, for example, at a temperature ranging from room temperature to about 40xc2x0 C., to incorporate the cyanoalkyl group. The resulting material is then reacted with hydrogen in the presence of a catalyst, such as Pd/C, in a solvent such as ethanol, for example, to form an amino nitrile, which is then reacted with ethoxycarbonylacetimidate hydrochloride under reflux conditions to form 1-cyanoethyl-2-(ethoxycarbonylmethyl) derivative 27. The cyanoalkyl derivative (27) is then hydrolyzed with ethanolic hydrochloric acid to form the 1-(ethoxycarbonylethyl)-2-(ethoxycarbonylmethyl) derivative (28). Reaction of the diester (28) with a base such as, for example, sodium ethoxide, yields the corresponding ethyl ester derivative (29). At this stage the N-5 nitrogen can be further substituted under basic conditions for those compounds of the invention where R2 is other than hydrogen. Reaction of the ethyl ester (29) with an amine such as, for example, 2,6-difluoroaniline, in a suitable solvent such as xylene, for example, at reflux temperatures yields the substituted benzimidazole-4-carboxamine derivative (10).
During any of the processes for preparation of the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.
To prepare the pharmaceutical compositions of this invention, one or more compounds or salts thereof, as the active ingredient, is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral. In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed. Thus for liquid oral preparations, such as for example, suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like; for solid oral preparations such as, for example, powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques. For parenterals, the carrier will usually comprise sterile water, though other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed. The pharmaceutical compositions herein will preferably contain per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, from about 0.5 to about 20 mg of the active ingredient, although other unit dosages may be employed.
In therapeutic use in treating disorders of the central nervous system in mammals, the compounds of this invention may be administered in an amount of from about 0.01 to 5 mg/kg per day. In therapeutic use as an anxiolytic, the compounds of the invention may be administered in an amount from about 0.01 to 5 mg/kg per day. In therapeutic use as an anticonvulsant/antiepileptic, the compounds of the invention may be administered in an amount from about 0.01 to 5 mg/kg per day. In therapeutic use as an agent for treating benzodiazepine overdoses, the compounds of the invention may be administered in an amount from about 0.01 to 5 mg/kg per day. In therapeutic use as a sedative/hypnotic, a therapeutically effective amount is from about 0.01 to 5 mg/kg per day. As a muscle relaxant about 0.01 to 5 mg/kg per day of the compounds of this invention may be used. Determination of optimum dosages and frequency of administration for a particular disease state or disorder is within the experimental capability of one skilled in the art.